Portable coagulation monitoring devices, systems, and methods

ABSTRACT

Portable coagulation monitoring devices, systems, and methods are disclosed. Namely, a test cartridge is provided for use in a portable coagulation monitor (PCM) device. Further, the test cartridge comprises two glass-filled thermoplastic polymer plates and a disposable blood introduction device. The two glass-filled thermoplastic polymer plates are arranged substantially in parallel with a small gap therebetween for receiving a sample of blood to be tested. Using the PCM device, the two glass-filled thermoplastic polymer plates can be moved linearly relative to each other. Methods of measuring coagulation response in a blood sample using the test cartridge and the PCM device are provided. A method of introducing blood into the test cartridge using the disposable blood introduction device is provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of and claims priority to U.S.patent application Ser. No. 14/717,117 entitled “Portable CoagulationMonitoring Devices, Systems, And Methods” filed on May 20, 2015. U.S.patent application Ser. No. 14/717,117 is a continuation of and claimspriority to PCT International Patent Application No. PCT/2014/065882entitled “Portable Coagulation Monitoring Devices, Systems, And Methods”filed on Nov. 17, 2014 and which is related and claims priority to U.S.Provisional Patent Application No. 61/904,523 entitled “Glass-FilledThermoplastic Polymer Plates for Measurement of BloodThromboelastography” filed on Nov. 15, 2013 and U.S. Provisional PatentApplication No. 61/904,489 entitled “Disposable Blood IntroductionSystem” filed on Nov. 15, 2013. U.S. patent application Ser. No.14/717,117 is also a continuation-in-part of and claims priority to U.S.patent application Ser. No. 13/897,712 entitled “Portable CoagulationMonitoring Device for Assessing Coagulation Response” filed on May 20,2013 (now U.S. Pat. No. 9,063,161 issued Jun. 23, 2015) which in turn isa divisional of and claims priority to U.S. patent application Ser. No.12/971,013 entitled “Portable Coagulation Monitoring Device and Methodof Assessing Coagulation Response” filed on Dec. 17, 2010 (now U.S. Pat.No. 8,450,078 issued May 28, 2013) which is related and claims priorityto U.S. Provisional Patent Application No. 61/287,780 entitled “PortableCoagulation Monitoring Device, System and Method of Use” filed on Dec.18, 2009. The entire disclosures of the aforementioned applications arespecifically incorporated by reference herein in their entirety.

TECHNICAL FIELD

The presently disclosed subject matter relates generally to bloodcoagulation monitoring methods and more particularly to portablecoagulation monitoring devices, systems, and methods including the useof glass-filled thermoplastic polymer plates and a disposable bloodintroduction device.

BACKGROUND

The process by which the body prevents blood loss is referred to ascoagulation. Coagulation involves the formation of a blood clot(thrombus) that prevents further blood loss from damaged tissues, bloodvessels or organs. The formation of a blood clot is a complicatedprocess involving a first system comprised of cells called plateletsthat circulate in the blood and serve to form a platelet plug overdamaged vessels and a second system based upon the actions of multipleproteins (called clotting factors) that act in concert to produce afibrin clot. These two systems work in concert to form a clot anddisorders in either system can yield disorders that cause either toomuch or too little clotting.

Platelets serve three primary functions: (1) sticking to the injuredblood vessel (a phenomenon called platelet adherence); (2) attaching toother platelets to enlarge the forming plug (a phenomenon calledplatelet aggregation); and (3) providing support for the processes ofthe coagulation cascade (molecules on the surface of platelets greatlyaccelerate several key reactions).

When a break in a blood vessel occurs, substances are exposed thatnormally are not in direct contact with the blood flow. These substances(primarily collagen and attached multimeric von Willibrand factor) allowthe platelets to adhere to the broken surface. Once a platelet adheresto the surface, it releases chemicals that attract additional plateletsto the damaged area, referred to as platelet aggregation. These twoprocesses are the first responses to stop bleeding. The protein-basedsystem (the coagulation cascade) serves to stabilize the plug that hasformed and further seal up the wound.

The support role of the platelet to the coagulation cascade is provided,in part, by one of the components on the outside of a platelet, calledphospholipids, which are required for many of the reactions in theclotting cascade. The goal of the cascade is to form fibrin, which willform a mesh within the platelet aggregate to stabilize the clot. All ofthe factors have an inactive and active form. Once activated, the factorwill serve to activate the next factor in the sequence until fibrin isformed. The coagulation cascade takes place at the site of a break in,e.g., a blood vessel that has the platelet aggregate. Fibrin forms amesh that, in concert with the platelets, plugs the break in the vesselwall. The fibrin mesh is then further stabilized by additional factorswhich cross-linkup the clot (much like forming an intricate network ofreinforced strands of fibrin).

In the case of trauma-induced bleeding, it is important to understandvery quickly the clotting response of a particular individual in orderto apply appropriate therapy to treat bleeding and ensure that thetrauma is dealt with appropriately. Defective platelet functions, bothprimary (adhesive, von Willibrand factor interaction) and secondary(fibrin polymer organization and polymerization, integrin function) arerecognized as a particularly important contributor in prolonged noncompressible bleeding. The development of hemostatic disorders in traumapatients, and associated progression in hemorrhagic and other shockstates, can be due to different factors and thus require differenttherapies.

Currently, thromboelastography (TEG) is the accepted clinical standardfor testing the efficiency of whole blood coagulation. As an example,the related U.S. Pat. No. 8,450,078, entitled “Portable CoagulationMonitoring Device and Method of Assessing Coagulation Response” (hereinincorporated in its entirety) discloses a portable coagulationmonitoring device typically comprising glass plates used to diagnosetrauma-related coagulopathies in the field. Further, current methods ofintroducing blood into, for example, a test cartridge of coagulationmonitoring devices may involve measuring the amount of blood requiredfor a test by using a pipette or other capillary device, for example,and then pipetting the required amount of blood into the test cartridge.Blood introduction and the need for clinical staff to pipette blood is achallenge in point-of-care settings and operating room settings wheresterility is important.

SUMMARY

In one aspect, the present invention discloses a device for measuringcoagulation response in a blood sample including: a set of testcomponents that include a first member having a first surface, and asecond member having a second surface, the first member positioned forhaving the first surface facing the second surface of the second member,and spaced an amount sufficient to allow a sample droplet of blood tocontact the first surface and the second surface and initiatecoagulation, and the first member and second member being linearlymovable relative to each other, wherein the first and second membersinclude a glass-filled thermoplastic polymer; a drive mechanismconnected to at least one of the first member and the second member forlinearly moving the first member and the second member relative to eachother in parallel when a blood sample is in contact with the firstsurface and the second surface; and an optical detection sensor systemfor detecting interaction of light with a blood sample located betweenthe first member and second member, as an indication of coagulationresponse of the blood sample.

In some embodiments, the first surface and the second surface are spacedapart from about 50 μm to about 250 μm. Moreover, the glass-filledthermoplastic polymer may be selected from the group consisting of nylon(polyamide), polycarbonate, polypropylene, polyethylene and polyester.The composition of the polymer may include glass beads and/or glassfibers in amounts including glass beads and/or fibers of about 5% toabout 60% in some examples, or about 30% in other examples.

In certain other embodiments, at least one of the first or secondmembers may be a rod that can rotate to initiate coagulation. In suchexamples, the device may further include a third member having a thirdsurface spaced an amount sufficient to allow a sample droplet of bloodto contact the surface of the rod and initiate coagulation.

Some aspects of the present disclosure include a blood sample collectioncartridge which is removable from the device and within which the testcomponents are housed. This test cartridge may be disposable after useand may further include a memory device for storing data relating to ablood sample tested. The blood sample collection cartridge may alsoinclude pinch contact ribs used to securely couple engagement featuresof the test components with the drive mechanism of the device.

The drive mechanism may be programmed for moving the first member andsecond member at different speeds relative to each other for detectingdifferent mechanisms involved in a coagulation response of a bloodsample. The drive mechanism may include piezo motors or any othersuitable driving source. The device may include a microcontroller forcontrolling operation of the drive mechanism and optical detectionsensor system. It may also include a displacement sensor for detectingand controlling the amount of relative movement between the first memberand the second member. Further still, the device may include aconnection interface module for connecting and communicating between thedevice and an external system, and an analog to digital convertercoupled to the optical detection sensor system for converting analogsignals indicative of coagulation response of a blood sample intodigital signals for storage thereof. In some embodiments, the device mayalso include a temperature control mechanism that may include a heaterand/or a cooling device.

The optical detector sensor system may be adapted for detecting bindingof the blood sample to the first surface and the second surface as anindication of platelet response during coagulation.

In some embodiments, the first and/or second surface has been treated toinduce, slow, or modify the coagulation process for selecting in favorof or against specific aspects of coagulation of the sample. Thetreatments may optionally enhance or reduce at least one characteristicselected from the group consisting of platelet or blood protein binding,reactivity, and activation. In general, the device is configured foranalyzing blood rheology and coagulation of fresh whole blood or somefraction thereof without adding external reagents. The device may alsobe configured for measuring, with no functional delay, the dynamicbalance between pro- and anti-thrombotic hemostatic status by sequentialsamples from the same person or animal.

In certain other embodiments, the device may include a first channel anda second channel, wherein the first channel comprises the set of testcomponents, the drive mechanism, and the optical detection sensorsystem, and the second channel comprises a second set of testcomponents, a second drive mechanism, and a second optical detectionsensor system, and further wherein the first and second channels operateindependently of one another and enable the device to performmeasurements of two blood samples at the same time. The separatechannels may be configured to perform distinct measurements that includeany one of a thrombelastogram test, a fibrinogen test, a heparin test,and other platelet function test.

In another aspect, the present invention discloses a method of measuringcoagulation response in a blood sample including the steps of: placing asample droplet of blood between and in contact with first and secondfacing surfaces of oppositely disposed glass-filled thermoplasticpolymer members; moving at least one member linearly with respect to theother member at a predetermined speed sufficient to activate plateletsthrough exposure to shear forces; and optically detecting, viameasurement of mechanical displacement, the interaction between thefirst and second surfaces resulting from changes in the viscosity of thesample fluid and binding to the member surfaces in order to measurecoagulation response of the droplet of blood. In some aspects, two bloodsample collection cartridges are used, wherein the first set of testcomponents are housed in a first cartridge representing part of a firstchannel and the second set of test components are housed in a secondcartridge representing part of a second channel.

In some aspects, the device may also include a humidity controlmechanism. In one example, the humidity control mechanism may include asponge-like pad inside a humidity pouch. The humidity pouch may alsoinclude a removable cover, thereby enabling the cover to be optionallyremoved to expose the sponge-like pad to an interior environment of thedevice.

In a further aspect, the present invention discloses a method ofmeasuring coagulation response in a blood sample including the steps of:placing a sample droplet of blood between and in contact with a firstsurface and a second surface of oppositely disposed glass-filledthermoplastic polymer members; moving at least one member linearly withrespect to the other member at a predetermined speed sufficient toactivate platelets through exposure to shear forces; and opticallydetecting, via measurement of mechanical displacement, the interactionbetween the first and second surfaces resulting from changes in theviscosity of the sample fluid and binding to the member surfaces inorder to measure coagulation response of the droplet of blood. In someembodiments, at least one member may be moved at a first speed andoptically detecting adherence of the sample droplet of blood to thesurface of the members to determine platelet response duringcoagulation. The method may also include subsequently moving at leastone member at a second speed slower than the first speed, and opticallydetecting the level of coagulation of the blood sample as indicative offibrin polymerization response.

The relative motion between the two members may be controlled togenerate arbitrarily selected waveforms to induce desired fluid shearrates at selected amplitudes, frequency, duration, and sequence suchthat the device is enabled to emulate fluid shear as desired over abroad range including from about DC (zero shear) to shear rates thatwould cause fluid cavitation and subsequent destruction of the cellularcomponents of the sample, and continuously including all points in theshear rate spectrum between these two points. The shear rate may also becontrolled in a sequence of values to generate specific protocols orplate motion paradigms for targeted diagnostic or analytic objectives,wherein such targeted diagnostic or analytic objectives include rapidinitiation of primary coagulation, destructive or non-destructiveviscoelastic evaluation of early, mid-phase, or late-phase clotting,emulation of clinically-accepted or otherwise recognized shear rateprotocols for comparison with other commercial or experimental devices,or validation testing against known standards.

Optical detection may be conducted by transmitting electromagnetic wavesinto the sample droplet, and detecting at least one of transmission,absorption, reflection and refraction of the electromagnetic wavesthrough the sample droplet at respective light detectors, to generateanalog signals representative of coagulation properties of the blood inthe sample droplet for primary and secondary coagulation mechanisms. Thesignals may also be converted to digital signals, stored, and analyzedin a predetermined manner to obtain selected information about thecoagulation response of the blood in the sample droplet.

In some embodiments, the method may include moving one member relativeto the other member in a manner causing the other member to move due tovisco elastic coupling between the blood and the other member; anddetermining the visco elastic properties of the blood from the movementof the other member. The method may also include detecting strain ratescaused by movement of the one member and the other member caused byvisco elastic coupling between the one member and the other membercaused by the blood sample; and determining the coagulation state of theblood by inference analysis based on visco elasticity of the bloodsample determined from mechanical coupling between the two members andthe resulting strain rates. The visco elasticity of the blood may becontinually measured over time to monitor changes of the coagulationresponse of the blood.

In a further aspect, the present invention discloses a method ofmeasuring coagulation response in a blood sample including the steps of:placing a sample droplet of blood between and in contact with facingsurfaces of oppositely disposed glass-filled thermoplastic polymermembers; moving at least one member linearly with respect to the othermember at a first speed; optically detecting a first coagulationresponse of the blood indicative of platelet response in the blood;moving at least one member linearly with respect to the other member ata second speed; and optically detecting a second coagulation response ofthe blood indicative of fibrin polymerization.

Other aspects of the present invention include a test cartridge for usewith a device for measuring coagulation response in a blood sample thatincludes a first member having a first surface, and a second memberhaving a second surface, the first member positioned for having thefirst surface facing the second surface of the second member, and spacedan amount sufficient to allow a sample droplet of blood to contact thefirst surface and the second surface and initiate coagulation, and thefirst member and second member being linearly movable relative to eachother, wherein the first and second members comprise a glass-filledthermoplastic polymer.

Other aspects further include a receptacle in the test cartridge for ablood introduction mechanism wherein the receptacle provides a path forthe sample droplet of blood to pass form the blood introductionmechanism to a point between the first surface and the second surface.The blood introduction mechanism may include an open top; a funnelportion; a flat bottom; and a lip attached to the funnel portion;wherein the open top comprises an opening larger than an opening at theflat bottom, and further wherein a desired amount of blood introduced tothe open top may pass through the blood introduction mechanism and intothe receptacle of the test cartridge, thereby providing the sampledroplet of blood into the device. The blood introduction mechanism mayalso include a solid plug cap attached wherein the solid plug capsealingly nests within the opening of the open top. The mechanism mayfurther include one or more alignment features disposed on the funnelportion.

Certain aspects of the presently disclosed subject matter having beenstated hereinabove, which are addressed in whole or in part by thepresently disclosed subject matter, other aspects will become evident asthe description proceeds when taken in connection with the accompanyingDrawings as best described herein below.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus described the presently disclosed subject matter in generalterms, reference will now be made to the accompanying Drawings, whichare not necessarily drawn to scale, and wherein:

FIG. 1 illustrates a simplified block diagram of an example of thepresently disclosed portable coagulation monitor (PCM) device comprisinga test cartridge having glass-filled thermoplastic polymer plates formeasurement of blood thromboelastography and a disposable bloodintroduction mechanism;

FIG. 2A and FIG. 2B illustrate perspective views of an example of thepresently disclosed test cartridge having glass-filled thermoplasticpolymer plates for measurement of blood thromboelastography and adisposable blood introduction mechanism;

FIG. 3A and FIG. 3B illustrate perspective views of the presentlydisclosed test cartridge with a portion of the housing removed andthereby revealing the internal components thereof;

FIG. 4A and FIG. 4B illustrate side views of the presently disclosedtest cartridge with a portion of the housing removed and therebyrevealing the internal components thereof;

FIG. 5A and FIG. 5B illustrate other perspective views of the presentlydisclosed test cartridge;

FIG. 6A and FIG. 6B illustrate side views of the presently disclosedtest cartridge with the housing entirely removed and showing only theinternal components thereof;

FIG. 7 illustrates an end view of the presently disclosed test cartridgewhen fully assembled;

FIG. 8 illustrates a perspective view of a pair of glass-filledthermoplastic polymer plates of the presently disclosed test cartridge;

FIG. 9 illustrates a perspective view of one of the glass-filledthermoplastic polymer plates of the presently disclosed test cartridge;

FIG. 10A and FIG. 10B illustrate end views of the plate carriers inrelation to a disposable blood introduction mechanism of the presentlydisclosed test cartridge;

FIG. 11A and FIG. 11B illustrate top down views of the plate carrierswith and without the disposable blood introduction mechanism of thepresently disclosed test cartridge;

FIG. 12 , FIG. 13 , and FIG. 14 show various detailed drawings of anexample of the disposable blood introduction mechanism of the presentlydisclosed test cartridge;

FIG. 15 illustrates a side view of an example of a glass-filledthermoplastic polymer rotation mechanism that can be used in place ofthe glass-filled thermoplastic polymer plates in the presently disclosedtest cartridge and/or PCM device;

FIG. 16 and FIG. 17 illustrate a perspective view and a plan view,respectively, of an example of the physical instantiation of the PCMdevice when holding the test cartridge;

FIG. 18 illustrates a perspective view of a portion of the PCM deviceshown in FIG. 16 and FIG. 17 ;

FIG. 19 illustrates a perspective view of a portion of the PCM deviceshown in FIG. 16 and FIG. 17 , but absent the test cartridge;

FIG. 20 illustrates an example of the actuator engagement mechanisms ofthe PCM device shown in FIG. 16 and FIG. 17 ;

FIG. 21 illustrates a perspective view of another example of a testcartridge;

FIG. 22 illustrates a perspective view of an example of a dual channelPCM device for receiving and holding two test cartridges;

FIG. 23 illustrates a flow diagram of an example of a method ofmeasuring coagulation response in a blood sample using the presentlydisclosed PCM device and/or test cartridge;

FIG. 24 illustrates a flow diagram of another example of a method ofmeasuring coagulation response in a blood sample using the presentlydisclosed PCM device and/or test cartridge; and

FIG. 25 illustrates a flow diagram of an example of a method ofintroducing blood into a test cartridge using the presently discloseddisposable blood introduction device.

DETAILED DESCRIPTION

The presently disclosed subject matter now will be described more fullyhereinafter with reference to the accompanying Drawings, in which some,but not all embodiments of the presently disclosed subject matter areshown. Like numbers refer to like elements throughout. The presentlydisclosed subject matter may be embodied in many different forms andshould not be construed as limited to the embodiments set forth herein;rather, these embodiments are provided so that this disclosure willsatisfy applicable legal requirements. Indeed, many modifications andother embodiments of the presently disclosed subject matter set forthherein will come to mind to one skilled in the art to which thepresently disclosed subject matter pertains having the benefit of theteachings presented in the foregoing descriptions and the associatedDrawings. Therefore, it is to be understood that the presently disclosedsubject matter is not to be limited to the specific embodimentsdisclosed and that modifications and other embodiments are intended tobe included within the scope of the appended claims.

In some embodiments, the presently disclosed subject matter providesportable coagulation monitoring devices, systems, and methods. Namely,the presently disclosed subject matter provides a test cartridge for usein a portable coagulation monitor (PCM) or assay device, wherein the PCMdevice is for the diagnosis of trauma or other related coagulopathies inwhich it is important to assess coagulation response to optimizetreatment, for example, in critical field situations wherein the firsthour is critical in terms of preventing long-term debilitating events oreven death.

The presently disclosed test cartridge is typically used inthromboelastigraphy (TEG) and includes, in some embodiments, two platesarranged substantially in parallel with a small gap therebetween forreceiving a sample of blood to be tested. The detection of coagulationmay be done, for example, optically by measuring mechanical interactionbetween the surfaces of the two plates resulting from changes in theviscosity of the sample fluid and binding of the sample fluid to theplate surfaces. In one example, the two plates are glass-filledthermoplastic polymer plates in which the surfaces face each other, andare spaced an amount sufficient to allow a relatively small sample ofblood to contact the facing surfaces of the two plates at the same timewithout an air space between. The glass-filled thermoplastic polymerplates may then be agitated to induce the platelet clotting process formeasurement of blood thromboelastigraphy.

Further, the presently disclosed test cartridge may include a disposableblood introduction device to dose the correct amount of blood into thetest cartridge using capillary action, without the need to measure theblood. The disposable blood introduction device may be used to fill thetest cartridge with the correct amount of blood and any extra blood inthe device may then be safely disposed of with the device. Thedisposable blood introduction device typically includes a funnel or thelike for introduction of the blood into the test cartridge and an outletto allow blood to move from the funnel into the test cartridge.

Referring now to FIG. 1 , a simplified block diagram is shown depictingan example of the presently disclosed portable coagulation monitor (PCM)device 100 that includes a test cartridge, wherein the test cartridgeincludes glass-filled thermoplastic polymer plates for measurement ofblood thromboelastography and a disposable blood introduction device.

PCM device 100 may be used for the diagnosis of trauma or other relatedcoagulopathies in which it is important to assess coagulation responseto optimize treatment, for example, in critical field situations whereinthe first hour is critical in terms of preventing long-term debilitatingevents or even death. In one example, PCM device 100 is based on the PCMdevice described with reference to U.S. Pat. No. 8,450,078, entitled“Portable Coagulation Monitoring Device and Method of AssessingCoagulation Response,” the entire disclosure of which is incorporatedherein by reference (“the '078 patent”). The '078 patent describes adevice, system and method in which small-volume blood samples may besubjected to shear forces and shear stresses between two parallel planarsurfaces to which linear motion trajectories are imparted. The formationof clots or coagulation of the sample is measured from dynamicmechanical coupling which occurs between the two parallel planarsurfaces. Detection of the coagulation response can be achieved throughoptical probing or by measurement of physical effects of the bloodsample binding to the planar surfaces, and restricting movement thereof.

In this example, PCM device 100 may include one or more of a powersource 106, a controller 108, a communications interface 110, a userinterface 112, an optics system 114, a temperature control mechanism116, and a pair of actuators 118 (e.g., actuators 118A, 118B). Thoseskilled in the art will recognize that PCM device 100 may include othercomponents, which are not shown, such as, but not limited to, any typesof motors, any types of sensors, any types of device-specific driversand/or controllers, data storage (i.e., volatile and/or nonvolatilememory), and the like.

Further, PCM device 100 can be ruggedized to allow for use duringimpacts and/or vibrations. In one example, PCM device 100 may include aninternal accelerometer (not shown) that can be used to measure suchimpacts and/or vibrations and allow PCM device 100 to compensateaccordingly. PCM device 100 may also be designed to be versatile andmeasure platelet and fibrin clotting over a wide dynamic range of shear.Additionally, PCM device 100 can operate on USB hub power as aperipheral device with components that are readily manufactured andassembled.

PCM device 100 may also include mechanical features (not shown) forreceiving and holding a test cartridge 120, for example, a TEG testcartridge. Namely, test cartridge 120 may be a pluggable component ofPCM device 100, as shown in FIG. 1 . Together, PCM device 100 and testcartridge 120 may be considered a PCM system. More details of an exampleof the physical instantiation of PCM device 100 for receiving andholding test cartridge 120 are shown and described hereinbelow withreference to FIG. 16 through FIG. 20 .

Power source 106 can be, for example, any rechargeable ornon-rechargeable battery. In one example, power source 106 is a 3.7-voltbattery, rated at about 96 mA and with a battery life of about 4 hours.In certain other embodiments, power source 106 may be external to thePCM device 100, or may include any suitable internal or external powersource.

Controller 108 can be any standard controller or microprocessor devicethat is capable of executing program instructions. Controller 108 can beused to manage the overall operations of PCM device 100 including thoseof communications interface 110, user interface 112, optics system 114,temperature control mechanism 116, and actuators 118.

Communications interface 110 may be any wired and/or wirelesscommunication interface for connecting to a network (not shown) and bywhich information may be exchanged with other devices connected to thenetwork. Examples of wired communication interfaces may include, but arenot limited to, USB ports, RS232 connectors, RJ45 connectors, Ethernet,and any combinations thereof. Examples of wireless communicationinterfaces may include, but are not limited to, an Intranet connection,Internet, ISM, Bluetooth® technology, Bluetooth® Low Energy (BLE)technology, Wi-Fi, Wi-Max, IEEE 402.11 technology, ZigBee technology,Z-Wave technology, 6LoWPAN technology (i.e., IPv6 over Low PowerWireless Area Network (6LoWPAN)), ANT or ANT+ (Advanced Network Tools)technology, radio frequency (RF), Infrared Data Association (IrDA)compatible protocols, Local Area Networks (LAN), Wide Area Networks(WAN), Shared Wireless Access Protocol (SWAP), any combinations thereof,and other types of wireless networking protocols.

User interface 112 can include any pushbutton controls, video display,touchscreen display, and/or any other types of visual, audible, and/ortactile indicators.

Optics system 114 can include, for example, a laser or other lightsource in combination with one or more optical detectors (or lightsensors).

Temperature control mechanism 116 can be any mechanism for maintainingtest cartridge 120 at a desired temperature (e.g., about 38° C.) duringuse. Temperature control mechanism 116 can be, for example, a peltiercooler or resistive heater. A heater controller and various feedbackmechanisms (e.g., negative temperature coefficient (NTC) thermistor, athermocouple device, and the like) may be associated with temperaturecontrol mechanism 116. Note further that the temperature controlmechanism 116 may be included either within the PCM device 100 or withinthe test cartridge 120.

Actuators 118 (e.g., actuators 118A, 118B) can be, for example, based onPiezo technology. In one example, actuators 118 are Piezo motors coupledto flexing ceramic actuators (see FIG. 16 , FIG. 17 , FIG. 18 ) having,for example, a displacement to about 2 mm, fast response in themillisecond range, nanometer resolution, and a low operating voltage. Inone example, actuators 118 are capable of delivering mechanical shear tothe blood sample over a wide dynamic range of mechanical oscillations offrom about 0.0001 Hz to about 1000 Hz. In certain other embodiments,actuators 188 may include voice coil motors, or any other motor suitablefor use in PCM device 100.

Test cartridge 120 may include two glass-filled thermoplastic polymerplates 122 (e.g., glass-filled thermoplastic polymer plates 122A, 122B)arranged substantially in parallel with each other and with a small gaptherebetween for receiving a sample of blood to be tested. The surfacesof glass-filled thermoplastic polymer plates 122A, 122B face each other,and are spaced an amount sufficient to allow a relatively small sampleof blood to contact the facing surfaces of glass-filled thermoplasticpolymer plates 122A, 122B at the same time without an air space between.

In some embodiments, actuator 118A is mechanically coupled toglass-filled thermoplastic polymer plate 122A and actuator 118B ismechanically coupled to glass-filled thermoplastic polymer plate 122B.Using actuators 118A, 118B of PCM device 100, glass-filled thermoplasticpolymer plates 122A, 122B can be agitated to induce the plateletclotting process for measurement of blood thromboelastigraphy. Namely,using actuators 118A, 118B, glass-filled thermoplastic polymer plates122A, 122B are movable relative to each other in a parallel and lineardirection, and the spacing is such that the components of blood caninitiate coagulation or adherence to each of the surfaces.

In test cartridge 120, the small gap between glass-filled thermoplasticpolymer plates 122A, 122B can be, for example, from about 50 μm to about250 μm. Using actuators 118A, 118B of PCM device 100, glass-filledthermoplastic polymer plates 122A, 122B slide past each other withcontrolled velocity to create a shear stress between the plates which isrepresented as T=μV/D where T equals shear stress, μ=viscosity, V=V1+V2,wherein V is equal to the relative linear velocity of the plates, andD=gap between the plates.

Using optics system 114, the coagulation response can be detected.Namely, optics system 114 may be used for detecting interaction of lightwith a blood sample located between glass-filled thermoplastic polymerplates 122A, 122B, with the interaction of light and detection thereofproviding an indication of coagulation response of the blood sample.More specifically, with appropriate positioning of a light source anddetectors (not shown), over time and in accordance with the variation ofthe movement of the glass-filled thermoplastic polymer plates 122A, 122Bto generate a particular shear rate, information about both plateletresponse, fibrin response, and other responses of the blood componentsduring coagulation can be obtained.

Using optics system 114, optical detection may be done by transmittinglight into the sample droplet, and detecting at least one oftransmission, reflection and refraction of the light through the sampledroplet at respective light detectors. Analog signals may be generatedfrom the detection at the light detectors representative of coagulationproperties of the blood in the sample droplet. Glass-filledthermoplastic polymer plates 122A, 122B are plates that are suitablytransparent to allow light transmission of about 90% or more of theincident light intensity. Namely, glass-filled thermoplastic polymerplates 122A, 122B are substantially optically transparent to allowoptical signals to pass through the blood sample allowing direct opticalvisualization of a portion or all of the blood sample between the planarsurfaces of glass-filled thermoplastic polymer plates 122A, 122B. Thisallows transmission, reflection, internal reflection, selectiveabsorption, polarization or optical rotation, frustrated internalreflection (either partial or total), and conduction of laser beams orother light sources.

In optics system 114, optical sensors are provided in position relativeto glass-filled thermoplastic polymer plates 122A, 122B of testcartridge 120 for detecting light being projected from, for example, alaser or other light source (not shown), through and into a samplebetween glass-filled thermoplastic polymer plates 122A, 122B. The lightcan then be detected as light transmitted through the sample, reflected,refracted or otherwise modified in the path through the sample, anddetected by optical sensors to obtain information about the coagulationproperties of the blood sample.

More specifically, PCM device 100 and test cartridge 120 allow for themeasurement of coagulation response based on the knowledge that thebiophysical response of blood depends in part on the relative shear ratebetween the blood and surfaces with which it is in contact. Morespecifically, the higher the shear rate, the greater the plateletresponse so that the platelets then stick to the surfaces of the plates,and thereby trigger the fibrin polymerization and couple the motion ofthe two plates when only one is driven by the actuators (e.g., 118A,118B). More specifically, it is recognized that in hemorrhaging eventsplatelets need to react quickly so the use of a high shear rate for ashort time period can allow accurate assessment of platelet response forthese conditions. Thereafter, lower shear rates can be employed in termsof relative movements of the plates or members with respect to eachother, to obtain an accurate assessment of fibrin response, or at anintermediate shear rate, both fibrin and platelet response.

“Shear” here is defined as the acceleration force felt by a particle inthe moving bulk flow of fluid (blood) at the interface with thestationary solid (face of the glass plates). The shear “rate” is thedifferential of velocities felt on different aspects of the particle'scross-sectional area and is dependent on the particle's distance fromthe stationary surface.

Test cartridge 120 may further include a humidity control mechanism 124.Humidity control mechanism 124 may be used to keep the inside of testcartridge 120 relatively moist, thereby slowing the drying time of theblood sample between glass-filled thermoplastic polymer plates 122A,122B. In one example, humidity control mechanism 124 is one or moresponge-like pads that are placed inside test cartridge 120, wherein thesponge-like pads are wetted, placed inside one or more sealed humiditypouches, and then installed in test cartridge 120. A user may thenoptionally open the humidity pouches to slow drying of the blood sample.Examples of the sponge-like pads are shown hereinbelow with reference toFIG. 3A through FIG. 7 .

Test cartridge 120 may further include a disposable blood introductiondevice 160. Disposable blood introduction device 160 is used to dose thecorrect amount of blood into test cartridge 120 using capillary action,without the need for a user to measure the blood. Disposable bloodintroduction device 160 may be used to fill test cartridge 120 with thecorrect amount of blood. Any extra blood in disposable bloodintroduction device 160 may then be safely disposed of together withdisposable blood introduction device 160. Disposable blood introductiondevice 160 typically includes a funnel or the like for introduction ofthe blood therein and a capillary at a flat bottom thereof that allowsblood to move from disposable blood introduction device 160 into testcartridge 120. More details of an example of test cartridge 120 areshown and described hereinbelow with reference to FIG. 2A through FIG.14 , with specific details of disposable blood introduction device 160shown in FIG. 12 , FIG. 13 , and FIG. 14 .

Referring now to FIG. 2A through FIG. 7 , various views are shown of anexample of the presently disclosed test cartridge 120 havingglass-filled thermoplastic polymer plates 122 for measurement of bloodthromboelastography and having disposable blood introduction device 160.Namely, FIG. 2A and FIG. 2B are perspective views of test cartridge 120when fully assembled; FIG. 3A and FIG. 3B are perspective views and FIG.4A and FIG. 4B are side views of test cartridge 120 with a portion ofthe housing removed and thereby revealing the internal componentsthereof; FIG. 5A and FIG. 5B are perspective views and FIG. 6A and FIG.6B are side views of test cartridge 120 without the housing thereof; andFIG. 7 is an end view of test cartridge 120 when assembled.

Referring now to FIG. 2A and FIG. 2B, test cartridge 120 comprises ahousing 132 for holding all the components thereof. In one example,housing 132 may be a two-piece housing, wherein the two pieces aresnap-fitted or adhered together. Housing 132 can be formed, for example,of molded plastic. One end of housing 132 can have a grip-like shape,while the opposite end of housing 132 can have an opening 142 throughwhich glass-filled thermoplastic polymer plates 122A, 122B can beengaged with actuators 118A, 118B of PCM device 100, which are typicallyexternal to test cartridge 120. Housing 132 may also have an opticswindow 150 in each side of housing 132. The optics windows 150substantially align with glass-filled thermoplastic polymer plates 122A,122B and are used by optics system 114 of PCM device 100 fortransmitting light in and out of test cartridge 120.

FIG. 2A and FIG. 2B also show disposable blood introduction device 160snap-fitted or press-fitted into housing 132 of test cartridge 120.Disposable blood introduction device 160 may include a fluid channel 162that is fluidly coupled to a fluid channel between glass-filledthermoplastic polymer plates 122A, 122B (see FIG. 10A and FIG. 10B). Acap 144 may also be provided for closing the opening that corresponds todisposable blood introduction device 160 when disposable bloodintroduction device 160 is not present in test cartridge 120. Cap 144can be, for example, pivotably coupled to housing 132.

Referring now to FIG. 3A through FIG. 7 , test cartridge 120 may furtherinclude a pair of movable plate carriers 134 for holding glass-filledthermoplastic polymer plates 122. For example, test cartridge 120 mayinclude plate carrier 134A for holding glass-filled thermoplasticpolymer plate 122A and plate carrier 134B for holding glass-filledthermoplastic polymer plate 122B. Each plate carrier 134 can be aflexible elongated member (e.g., a thermoplastic member). One end of theelongated member can be held stationary in housing 132 and the other endcan include a frame for holding glass-filled thermoplastic polymer plate122, wherein the frame portion of each plate carrier 134 issubstantially floating in midair. Accordingly, the frame portion ofplate carrier 134 that is holding glass-filled thermoplastic polymerplate 122 may be movable. More particularly, the frame portion of platecarrier 134A may be movable in a parallel and linear direction withrespect to the frame portion of plate carrier 134B.

Additionally, the frame portion of plate carrier 134 may include anengagement feature 136. Namely, plate carrier 134A may includeengagement feature 136A and plate carrier 134B may include engagementfeature 136B (see FIG. 7 ). Engagement features 136A, 136B areaccessible through opening 142 of housing 132 and can be mechanicallyengaged with actuators 118A, 118B of PCM device 100.

The frame portion of plate carrier 134 is typically shaped according tothe shape of glass-filled thermoplastic polymer plate 122. In oneexample, glass-filled thermoplastic polymer plate 122 is a circulardisc. However, glass-filled thermoplastic polymer plate 122 andaccordingly the frame portion of plate carrier 134 can be any shape,such as circular, ovular, square, rectangular, triangular, polygonal,and the like.

Referring still to FIG. 3A through FIG. 6B, test cartridge 120 may alsoinclude a pair of humidity pads 146 (e.g., humidity pads 146A, 146B).Humidity pads 146A, 146B are one example of humidity control mechanism124 of test cartridge 120 as described in FIG. 1 . For example, humiditypads 146A, 146B may be sponge-like pads that are placed inside testcartridge 120, wherein the sponge-like pads are wetted and theninstalled in test cartridge 120. Humidity pads 146A, 146B are used tokeep the inside of test cartridge 120 relatively moist and to slow thedrying time of the blood sample between glass-filled thermoplasticpolymer plates 122A, 122B. Test cartridge 120 is not limited to twohumidity pads 146. Test cartridge 120 can include any number of humiditypads 146.

In some embodiments, each of the humidity pads 146 may be provided in ahumidity pouch that is sealed, for example, using a foil seal forstorage, but that can be peeled away when test cartridge 120 is readyfor use. Accordingly, a pull tab 148 can be provided with each humiditypad 146 for pulling away the foil seal and exposing humidity pad 146. Inthe exemplary embodiment shown in, e.g., FIG. 3A and FIG. 3B, humiditypad 146A has a pull tab 148A and humidity pad 146B has a pull tab 148B.FIG. 4A, FIG. 4B, and FIG. 5B, and FIG. 6B show test cartridge 120 withpull tabs 148A, 148B removed and humidity pads 146A, 146B exposed.

With each test using test cartridge 120, a certain disposable bloodintroduction device 160 may be installed and the blood sample introducedinto the gap between glass-filled thermoplastic polymer plates 122A,122B. Upon completing the blood introduction between glass-filledthermoplastic polymer plates 122A, 122B the disposable bloodintroduction device 160 may be removed and cap 144 secured. For example,FIG. 4A shows disposable blood introduction device 160 installed in testcartridge 120, whereas FIG. 4B shows disposable blood introductiondevice 160 not installed in test cartridge 120 and cap 144 secured.

Further, FIG. 5B shows the process of fitting disposable bloodintroduction device 160 into a blood introduction channel 140 formed bythe arrangement of plate carriers 134A, 134B. Namely, an outlet ofdisposable blood introduction device 160 may be press-fitted orsnap-fitted into blood introduction channel 140, then blood may flowfrom fluid channel 162 of disposable blood introduction device 160 intoblood introduction channel 140, and then into the gap betweenglass-filled thermoplastic polymer plates 122A, 122B.

Referring now to FIG. 8 , which is a perspective view of a pair ofglass-filled thermoplastic polymer plates 122, and FIG. 9 which is aperspective view of one glass-filled thermoplastic polymer plate 122,each plate carrier 134 may include a flexing portion 138. Plate carriers134A, 134B are designed and positioned to hold the planar glass-filledthermoplastic polymer plates 122A, 122B substantially parallel and witha small gap in between for holding, for example, a blood sample 190.Namely, the frame portion of plate carrier 134A is movable in a paralleland linear direction with respect to the frame portion of plate carrier134B. The spacing of glass-filled thermoplastic polymer plates 122A,122B in plate carriers 134A, 134B is such that the components of bloodcan initiate coagulation or adherence to each of the surfaces. Forexample, the small gap between glass-filled thermoplastic polymer plates122A, 122B can be, for example, from about 50 μm to about 250 μm.

Further, the shape of engagement features 136 is designed to inhibitspreading when in use. Additionally, in one example, each glass-filledthermoplastic polymer plate 122 has a diameter d of about 20 mm (seeFIG. 9 ).

The glass constituent in glass-filled thermoplastic polymer plates 122activates the platelets and induces blood clotting. The thermoplasticcarrier (e.g., plate carriers 134) allows the test cartridge 120 designto incorporate disposable blood introduction device 160, allowscustom-made shaping to maximize sensitivity and assay accuracy,minimizes the number of components in test cartridge 120, minimizescosts, and allows for numerous mechanisms of platelet activation. Thereis no need for multiple components or the use of whole glass discs.

The polymers used in glass-filled thermoplastic polymer plates 122 canbe a variety of polymers, such as nylon (polyamide), polycarbonate,polypropylene, polyethylene and polyester. Accordingly, in someembodiments, the glass-filled thermoplastic polymer is selected from thegroup consisting of nylon (polyamide), polycarbonate, polypropylene,polyethylene and polyester. In some embodiments, the amount of glasswithin the polymer can be between about 5% to about 60%. In otherembodiments, the amount of glass within the polymer is about 30%.Accordingly, in some embodiments, the glass-filled thermoplastic polymercontains glass beads and/or glass fibers and the amount of glass beadsand/or glass fibers within the glass-filled thermoplastic polymer isbetween about 5% to about 60%. In other embodiments, the amount of glassbeads and/or glass fibers within the glass-filled thermoplastic polymeris about 30%.

In some embodiments, the glass in glass-filled thermoplastic polymerplates 122 can be found as fibers, beads, irregular pieces, or any formthat activates the platelets in blood and induces blood clotting. Inother embodiments, glass-filled thermoplastic polymer plates 122 areinjection molded. In still other embodiments, glass-filled thermoplasticpolymer plates 122 can be designed with intricate three-dimensionalstructures, such as thin channels, capillaries, undercuts and/or holesdepending on the specific applications of the device.

In further embodiments, test cartridge 120 may further include at leastone structure selected from the group consisting of a channel, acapillary, an undercut, and a hole. For example, a blood introductionsystem that includes a capillary or channel can be fully incorporatedinto the design of test cartridge 120, allowing for test cartridge 120to be used as a diagnostic test. In this example, the capillary plateand linkage arms are one single piece and therefore the capillary orchannel is molded in one step. The inclusion of disposable bloodintroduction device 160 allows the blood of a subject to be addeddirectly into test cartridge 120 without the need for external pipettesbecause the blood is delivered directly to the capillary/measurementarea. Additionally, there is no need to measure or dose the bloodbecause the correct amount of blood is delivered to the clot measurementarea. In some embodiments, the glass-filled thermoplastic polymers canbe used for the simultaneous introduction of blood samples and themeasurement of clotting (including platelet activation and extrinsicpathways) in the measurement of blood thromboelastography. In otherembodiments, the first glass-filled thermoplastic polymer plate 122A andsecond glass-filled thermoplastic polymer plate 122B of test cartridge120 make up a blood sample collection cartridge which is removable fromPCM device 100. In still other embodiments, PCM device 100 furtherincludes a memory device for storing data relating to a blood sampletested.

In some embodiments, the first and/or the second surface of theglass-filled thermoplastic polymer plates 122 have been treated toinduce, slow, or modify the coagulation process for selecting in favorof or against specific aspects of coagulation of the sample. In otherembodiments, treatment of the surfaces of the glass-filled thermoplasticpolymer plates 122 enhances at least one characteristic selected fromthe group consisting of platelet or blood protein binding, reactivity,and activation. In yet other embodiments, the treatment of the surfacesreduces at least one characteristic selected from the group consistingof platelet or blood protein binding, reactivity, and activation. Infurther embodiments, PCM device 100 and/or test cartridge 120 areconfigured for analyzing blood rheology and coagulation of fresh wholeblood or some fraction thereof without adding external reagents. Instill other embodiments, PCM device 100 and/or test cartridge 120 areconfigured for measuring with no functional delay the dynamic balancebetween pro- and anti-thrombotic hemostatic status by sequential samplesfrom the same person or animal.

Referring now to FIG. 10A and FIG. 10B and to FIG. 11A and FIG. 11B, endviews and top down views, respectively, are shown to illustrate moredetails of disposable blood introduction device 160 in relation to thepair of plate carriers 134 of the presently disclosed test cartridge120. Disposable blood introduction device 160 may include a grip portion164 and a funnel portion 166 that includes fluid channel 162. Further,disposable blood introduction device 160 may have an inlet 168 and anoutlet 170. As funnel portion 166 is tapered, the opening that is inlet168 is larger than the opening that is outlet 170. Additionally, a pairof alignment features 172 may be provided on funnel portion 166. Wheninstalled, outlet 170 may be fitted into blood introduction channel 140formed by plate carriers 134A, 134B and with alignment features 172fitted against plate carriers 134A, 134B. FIG. 12 , FIG. 13 , and FIG.14 show various detailed drawings of an example of disposable bloodintroduction device 160 of the presently disclosed test cartridge 120.All exemplary dimensions shown in FIG. 13 and FIG. 14 are in millimeters(mm). In one example, the diameter of inlet 168 of disposable bloodintroduction device 160 is about 8 mm, the diameter of outlet 170 isabout 1.5 mm, and the narrowest portion of fluid channel 162 has adiameter of about 0.6 mm (see FIG. 14 ).

Accordingly, disposable blood introduction device 160 can provide ahollow tube of disposable material that includes, in some embodiments:a) an open top (e.g., inlet 168); b) an upper cylindrical portion offunnel portion 166; c) a frustoconical portion of funnel portion 166; d)a lower cylindrical portion of funnel portion 166; d) a flat bottom atoutlet 170; and e) a lip (e.g., grip portion 164) attached to the uppercylindrical portion and/or to the frustoconical portion. Further, thewall thickness of funnel portion 166 gradually tapers from inlet 168 tooutlet 170. Additionally, disposable blood introduction device 160 caninclude a solid plug cap (not shown), which is attached to, for example,grip portion 164; wherein the solid plug cap sealingly nests withininlet 168.

Disposable blood introduction device 160 can be formed, for example, ofany kind of polymer or glass material that can hold blood and allows theblood at the bottom of the device to move into test cartridge 120 wheninstalled. Disposable material can be sterilized before use. Examples ofmaterials include nylon (polyamide), polycarbonate, polypropylene,polyethylene, polyester, and the like.

In operation, blood is introduced to disposable blood introductiondevice 160 through inlet 168. Funnel portion 166 and the fluid channel162 therein go from a larger diameter at the inlet 168 of disposableblood introduction device 160 to a smaller diameter near the outlet 170of disposable blood introduction device 160. The smaller diameter at theoutlet 170 of disposable blood introduction device 160 allows a smallamount of blood to move out of disposable blood introduction device 160at a time and into test cartridge 120, when installed, in a measuredmanner. Once the blood intake area of test cartridge 120 is full, bloodno longer moves from disposable blood introduction device 160 into testcartridge 120. Accordingly, disposable blood introduction device 160allows the blood to automatically dose into test cartridge 120. In someembodiments, the smaller diameter near the outlet 170 of disposableblood introduction device 160 is small enough so that blood does notmove from disposable blood introduction device 160 unless disposableblood introduction device 160 is contacted with the blood intake area oftest cartridge 120 (i.e., through capillary action).

For purposes of this disclosure, it should be noted that by “blood” ismeant a mixture of whole blood with one or more substances, a fractionof whole blood containing one or more of the constituents of wholeblood, a fraction of whole blood mixed with one or more non bloodsubstances, or a purified blood constituent, such as blood platelets orserum, a reconstituted blood preparation, a modified blood sample, or ablood substitute.

Blood can be added to disposable blood introduction device 160 using apipette tip or a syringe. However, in some embodiments, the blood isadded to disposable blood introduction device 160 directly from the bodyof a subject, such as by using a capillary blood collection (fingerprick) method. The finger can be punctured by using any of a variety ofpuncture or incision devices. In other embodiments, the blood is addedto disposable blood introduction device 160 from a storage container,such as from a tube, bottle, and the like, by using an alternativemeans, such as by using a pipette tip, for example. This may benecessary if the blood is stored before being tested, such as after avenous blood draw, for example. Excess or unused blood is removed bydetaching disposable blood introduction device 160 from the testcartridge.

Disposable blood introduction device 160 minimizes excess blood, allowsblood to be added without measurement/pipetting and allows removal ofexcess blood, thereby reducing contamination risk from the unused blood.Therefore, disposable blood introduction device 160 can be used inpoint-of-care settings, such as in the field, operating room, or inemergency situations.

Referring now to FIG. 15 , a side view is shown of an example of aglass-filled thermoplastic polymer rotation mechanism 1500 that can beused in place of the glass-filled thermoplastic polymer plates 122 inthe presently disclosed PCM device 100 and/or test cartridge 120. Inthis example, glass-filled thermoplastic polymer rotation mechanism 1500comprises a housing 1510 with a central bore 1512 (e.g., a taperedcentral bore) and an inner rod 1514. Housing 1510 is a glass-filledthermoplastic polymer housing and inner rod 1514 is a glass-filledthermoplastic polymer rod.

Inner rod 1514 can be rotated relative to central bore 1512 in housing1510. In this embodiment, at least one member of the device is a rod(e.g., inner rod 1514) that can rotate to initiate coagulation. In thiscase, glass-filled thermoplastic polymer rotation mechanism 1500 can beused for a simple two component test in which blood (e.g., blood sample190) is sandwiched between housing 1510 and inner rod 1514. Namely, adrop of blood is provided at the inlet of central bore 1512, then theblood flows by capillary action between housing 1510 and inner rod 1514.

The glass-filled thermoplastic polymer inner rod 1514 and theglass-filled thermoplastic polymer housing 1510 rotate relative to eachother creating a shear force on the blood and, coupled with the glassactivation, allow a clot to be measured by a load cell, electricalresistance, and/or torque measurements. In one example, inner rod 1514and housing 1510 have a clearance of from about 20 μm to about 200 um.In other embodiments, glass-filled thermoplastic polymer rotationmechanism 1500 further comprises a third member having a third surfacespaced an amount sufficient to allow a sample droplet of blood tocontact the surface of inner rod 1514 and initiate coagulation.

Referring now to FIG. 16 and FIG. 17 , a perspective view and a planview, respectively, are shown of one example of the physicalinstantiation of PCM device 100 when holding test cartridge 120.Additionally, FIG. 18 shows a close-up view of a portion of theexemplary PCM device 100 shown in FIG. 16 and FIG. 17 . In this example,PCM device 100 comprises a base plate 210 that has multiplethrough-holes 212. The multiple through-holes 212 can be used, forexample, to attach a cover (not shown) or any other mechanisms to baseplate 210. Base plate 210 can be formed, for example, of molded plasticor aluminum.

In some embodiments, a pair of alignment blocks 214 are mounted on baseplate 210 between which housing 132 of test cartridge 120 can be snugglyfitted. A guide rail mounting bracket 216 that supports a pair offloating linear guide rails 218 that are coupled to a pair ofreceptacles 220 may also be mounted on base plate 210, wherein the pairof receptacles 220 are designed to physically couple to engagementfeatures 136A, 136B of plate carriers 134A, 134B of test cartridge 120(see FIG. 18 ). More details of receptacles 220 and engagement features136 are shown and described hereinbelow with reference to FIG. 20 .

Actuators 118 (e.g., Piezo actuators) may also be mounted on base plate210 and may be mechanically coupled to receptacles 220 via the floatinglinear guide rails 218. Further, a pair of proximity sensors 222 (e.g.,induction proximity sensors) may be mounted on base plate 210. Proximitysensors 222 may be used to sense the positions of the floating linearguide rails 218. Further, an electronics housing 224 may be mounted onbase plate 210. Electronics housing 224 contains any control electronicsassociated with PCM device 100, such as any of the electronics describedhereinabove with reference to FIG. 1 .

Referring now to FIG. 19 , a perspective view is shown of a portion ofPCM device 100 shown in FIG. 16 and FIG. 17 , but absent test cartridge120. Namely, FIG. 19 shows a cavity 226 that may be formed in base plate210. The footprint of cavity 226 is substantially the same as the shapeof housing 132 of test cartridge 120, whereas test cartridge 120 restsin cavity 226 when installed in PCM device 100.

Referring now to FIG. 20 , an example is shown of the actuatorengagement mechanisms of PCM device 100 shown in FIG. 16 and FIG. 17 .Namely, FIG. 20 shows a plan view of an example of one of thereceptacles 220. In this example, receptacle 220 has a horseshoe type ofshape. Two pinch contact ribs 221 are provided on the two “fingers,”respectively, of receptacle 220. Pinch contact ribs 221 ensure reliableengagement with engagement features 136 of plate carriers 134 of testcartridge 120. To further ensure reliable engagement, engagement feature136 of plate carriers 134 of test cartridge 120 may also include a ridge137, which provides a point contact with receptacle 220.

Referring now to FIG. 21 , a perspective view is shown of anotherexample of a test cartridge 120 that includes glass-filled thermoplasticpolymer plates 122.

Referring now to FIG. 22 , a perspective view is shown of an example ofa dual channel PCM device 2200 for receiving and holding two testcartridges 120. Namely, dual channel PCM device 2200 provides thecapability to receive two test cartridges 120 and includes the hardwarenecessary to run two tests simultaneously.

In some embodiments, dual channel PCM device 2200 includes a housing orassembly 2210 that is designed to receive and process two testcartridges 120. Namely, housing 2210 has a first opening 2212 forreceiving the first test cartridge 120A and a second opening 2214 forreceiving the second test cartridge 120B. Dual channel PCM device 2200includes substantially the same components and functionality that isdescribed hereinabove with reference to FIG. 1 and FIG. 16 through FIG.18 , except duplicate components and/or hardware are included in orderto support two test cartridges 120 simultaneously. Accordingly, dualchannel PCM device 2200 has a first channel (i.e., channel one) and asecond channel (i.e., channel two).

Using dual channel PCM device 2200, two tests can be run simultaneously.For example, dual channel PCM device 2200 allows one of two scenarios:(1) a time delayed thrombelastogram relative to a first test (i.e., tomake a comparison to evaluate effectiveness of treatment, etc.) or (2)two distinct tests (e.g., thrombelastogram and fibrinogen test, orheparin, other platelet function, etc.). Note that the dual tests may berun simultaneously, at different times, or at overlapping times (i.e.the second test is begun while the first test is running).

Using the single channel PCM device 100 and/or dual channel PCM device2200, a number of different test cartridges 120 with added “chemistry”for fibrinogen testing (or heparin and other platelet function tests asextras) would allow the emergency trauma, cardiology, and vascularclinicians a full suite of clinical diagnostics relevant to theirrequirements. One advantage is to be able to run either standard wholevenous blood, a parallel fibrinogen test, or a second time delayedstandard to monitor therapeutic change/response.

The ability to run a second test cartridge within the same PCM device(e.g., dual channel PCM device 2200), either with, or without“chemistry,” would leverage all the current technology and also provideadditional clinical information. However, this could be more flexiblethan current technology, and also allow near patient clinicalresponsiveness to additional diagnostic requirements or to monitortherapeutic response. This would be useful as it would take thefunctionality and versatility of current devices but truly make it pointof care as it would be accessible without the pipetting steps.

Running a second standard sample within the same PCM device adds theability to see a new curve on the same patient, run either after atherapeutic change—i.e., plasma administration, or a significant changein clinical condition alongside the first trace for direct comparisonwithout stopping the first test or requiring a second PCM device.

Using, for example, dual channel PCM device 2200, the time delayedtraces can be displayed on the same screen at the same time. Channel twocould also be used to run a cartridge with “chemistry” as previouslydiscussed. The key opportunities for the additional chemistry include:

(1) Fibrinogen is an important test that essentially knocks out allplatelet function and therefore tests only clottable protein function.Fibrinogen is increasingly being seen as a key test in establishingpatient hemostasis. Additionally, therapeutic interventions are nowbeing based on this test.

(2) Other chemistry tests could include: (a) a tissue factor activatedtest similar to ExTEM and rapid TEG; (b) a heparinase test to allowcomparison of a prolonged test with a heparin excluded sample (this ismost useful in cardiac theater but is occasionally of use in otherareas); and (c) a platelet function test which is the other test offeredas “bolt-ons” for TEG and RoTEM. This could also include function andplatelet count tests.

“Bog standard” platelet function analyzers aim to work in a similar way,but some analyzers use chemistry to test specific platelet activationreceptor function (ADP, Cyclo ox), which can determine whether aspirinor clopidogrel are actually working. This could also be incorporatedwithin the presently disclosed PCM devices, so long as additional“chemistry” is introduced.

In addition to coagulation tests, non-clotting tests may also beperformed. For example, with respect to hemoglobin, the addition of anear patient hemoglobin assay to a thrombelastogram would be very usefulto the clinician, as it is currently also requested. It is possible tointroduce an optical test through the glass-filled thermoplastic polymerplates 122 on the same sample, which would reduce time lag or thereliance on another near patient test. Further, incorporating a separateassay into the same device would therefore be beneficial.

With respect to blood glucose, blood glucose is often tested inhemorrhage situations, and although the technology is widespread, acombined glucose oxidase electrochemical sensor could provide theinformation more simply than current practices. Current practice is toeither use a separate monitor using capillary blood or measure glucoseas part of an arterial blood gas analysis (which, in practice, is notideal).

With respect to arterial blood gas analysis, arterial blood gasanalyzers have moved out of the lab and into the critical care areasover the last 10-15 years. There is an added advantage to the presentlydisclosed PCM devices in that repeated samples are essentially looked atduring major cases in a similar way to repeat clotting.

The presently disclosed PCM Device 100 or 2200 may also be used toconduct Hb and platelet count tests. Using, for example, dual channelPCM device 2200, Hb and platelet count tests can be performed in situusing glass-filled thermoplastic polymer plates 122. Advantages include:(1) an optical check can be performed on the exact sample forcoagulation, (2) it eliminates variation between blooddraw/fingerstick-venous-arterial/non-pipetting, (3) it eliminates theneed for additional tests (e.g., lab tests or hemo-cue), (4)anemia/vascular packers, and (5) platelet count test (also using opticalplates 122).

Referring now to FIG. 23 , a flow diagram is presented of an example ofa method 2300 of measuring coagulation response in a blood sample using,for example, PCM device 100 and test cartridge 120. Method 2300 mayinclude, but is not limited to, the following steps.

At a step 2310, a sample droplet of blood is placed between and incontact with the first and second facing surfaces of oppositely disposedglass-filled thermoplastic polymer plates 122 of test cartridge 120. Inone example, disposable blood introduction device 160 is used to placethe blood sample between glass-filled thermoplastic polymer plates 122Aand 122B.

At a step 2315, at least one glass-filled thermoplastic polymer plate122 is moved linearly with respect to the other glass-filledthermoplastic polymer plate 122 at a predetermined speed sufficient toactivate platelets through exposure to shear forces. In one example,actuator 118A of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122A linearly with respect to glass-filledthermoplastic polymer plate 122B at a predetermined speed sufficient toactivate platelets through exposure to shear forces. In another example,actuator 118B of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122B linearly with respect to glass-filledthermoplastic polymer plate 122A at a predetermined speed sufficient toactivate platelets through exposure to shear forces. In yet anotherexample, actuators 118A and 118B of PCM device 100 are used to move bothglass-filled thermoplastic polymer plates 122A and 122B linearly withrespect to each other at a predetermined speed sufficient to activateplatelets through exposure to shear forces.

At a step 2320, using, for example, optics system 114 of PCM device 100,an optical detection operation is performed (i.e., via measurement ofmechanical displacement) of the interaction between the surfaces ofglass-filled thermoplastic polymer plates 122A, 122B, resulting fromchanges in the viscosity of the sample fluid and binding to the surfacesin order to measure coagulation response of the droplet of blood.

Referring now to FIG. 24 , a flow diagram is presented of a method 2400,which is another example of a method of measuring coagulation responsein a blood sample using, for example, PCM device 100 and test cartridge120. Method 2400 may include, but is not limited to, the followingsteps.

At a step 2410, a sample droplet of blood is placed between and incontact with the first and second facing surfaces of the oppositelydisposed glass-filled thermoplastic polymer plates 122 of test cartridge120. In one example, disposable blood introduction device 160 is used toplace the blood sample between glass-filled thermoplastic polymer plates122A and 122B.

At a step 2415, at least one glass-filled thermoplastic polymer plate122 is moved linearly with respect to the other glass-filledthermoplastic polymer plate 122 at a first speed. In one example,actuator 118A of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122A linearly with respect to glass-filledthermoplastic polymer plate 122B at a first speed. In another example,actuator 118B of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122B linearly with respect to glass-filledthermoplastic polymer plate 122A at a first speed. In yet anotherexample, actuators 118A and 118B of PCM device 100 are used to move bothglass-filled thermoplastic polymer plates 122A and 122B linearly withrespect to each other at a first speed.

At a step 2420, using, for example, optics system 114 of PCM device 100,a first coagulation response of the blood indicative of plateletresponse in the blood is optically detected.

At a step 2425, at least one glass-filled thermoplastic polymer plate122 is moved linearly with respect to the other glass-filledthermoplastic polymer plate 122 at a second speed. In one example,actuator 118A of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122A linearly with respect to glass-filledthermoplastic polymer plate 122B at a second speed. In another example,actuator 118B of PCM device 100 is used to move glass-filledthermoplastic polymer plate 122B linearly with respect to glass-filledthermoplastic polymer plate 122A at a second speed. In yet anotherexample, actuators 118A and 118B of PCM device 100 are used to move bothglass-filled thermoplastic polymer plates 122A and 122B linearly withrespect to each other at a second speed.

At a step 2430, using, for example, optics system 114 of PCM device 100,a second coagulation response of the blood indicative of fibrinpolymerization is optically detected.

In method 2300 of FIG. 23 and/or method 2400 of FIG. 24 , to detect twodifferent types of coagulation response, glass-filled thermoplasticpolymer plates 122 can be moved relative to each other at a first speedand a response optically detected, and thereafter moved at a secondspeed which is slower than the first speed and a second responseoptically detected, typically fibrin polymerization. In addition, in thecase where only one glass-filled thermoplastic polymer plate 122 ismoved, it should be appreciated that the visco elastic response of theblood sample on the surfaces of both glass-filled thermoplastic polymerplates 122 can cause the movement of the first glass-filledthermoplastic polymer plate 122 to induce movement of the secondglass-filled thermoplastic polymer plate 122 (“coupled motion”), whichcan be measured as indicative of visco elastic response of the blood,ultimately leading to conclusions which may be inferred relative tocoagulation response. Moreover, by moving glass-filled thermoplasticpolymer plates 122 at different speeds over time, changes in the viscoelastic state of the blood sample may be measured as a clot is formed,which is also indicative of coagulation response.

In some embodiments, method 2300 of FIG. 23 and/or method 2400 of FIG.24 include moving one glass-filled thermoplastic polymer plate 122relative to the other glass-filled thermoplastic polymer plate 122 in amanner causing the other glass-filled thermoplastic polymer plate 122 tomove because of visco elastic coupling between the blood and the otherglass-filled thermoplastic polymer plate 122; and determining the viscoelastic properties of the blood from the movement of the otherglass-filled thermoplastic polymer plate 122. In other embodiments, themethod further includes detecting strain rates caused by movement of theone glass-filled thermoplastic polymer plate 122 and the otherglass-filled thermoplastic polymer plate 122 caused by visco elasticcoupling between the one glass-filled thermoplastic polymer plate 122and the other glass-filled thermoplastic polymer plate 122 caused by theblood sample; and determining the coagulation state of the blood byinference analysis based on visco elasticity of the blood sampledetermined from mechanical coupling between the two glass-filledthermoplastic polymer plates 122 and the resulting strain rates. Instill other embodiments, method 2300 of FIG. 23 and/or method 2400 ofFIG. 24 further include continually measuring the visco elasticity ofthe blood over time to monitor changes over time of the coagulationresponse of the blood. In some embodiments, the sample droplet of bloodcomes directly from the body of a subject.

In other embodiments, PCM device 100, dual channel PCM device 2200,and/or test cartridge 120 can be used in measurement of the viscosity ofa multitude of fluids other than blood, including non-biological fluids.For example, using devices and methods similar to those taught herein,the viscosity of any number of other fluids, including non-biologicalfluids, can be measured for significantly less than current measurementmethods.

Referring now to FIG. 25 is a flow diagram of an example of a method2500 of introducing blood into a test cartridge (e.g., test cartridge120) using the presently disclosed disposable blood introduction device160. Method 2500 may include, but is not limited to, the followingsteps.

At a step 2510, the disposable blood introduction device 160 of thepresent invention is inserted into test cartridge 120. For example, theoutlet end 170 of disposable blood introduction device 160 is insertedinto blood introduction channel 140 formed by the arrangement of platecarriers 134A, 134B in test cartridge 120.

At a step 2515, a droplet of blood is inserted into inlet 168 ofdisposable blood introduction device 160 and then the blood flows intofluid channel 162 of disposable blood introduction device 160 bycapillary action.

At a step 2520, the blood is allowed to move from disposable bloodintroduction device 160 into test cartridge 120 until the blood stopsmoving. Namely, by capillary action blood flows from disposable bloodintroduction device 160 into the gap between glass-filled thermoplasticpolymer plates 122A, 122B of test cartridge 120. When the gap betweenglass-filled thermoplastic polymer plates 122A, 122B is filled withblood, the blood flow from disposable blood introduction device 160automatically stops.

At a step 2525, disposable blood introduction device 160 is removed fromtest cartridge 120 after the blood has stopped moving into testcartridge 120.

Following long-standing patent law convention, the terms “a,” “an,” and“the” refer to “one or more” when used in this application, includingthe claims. Thus, for example, reference to “a subject” includes aplurality of subjects, unless the context clearly is to the contrary(e.g., a plurality of subjects), and so forth.

Throughout this specification and the claims, the terms “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise. Likewise, the term “include” andits grammatical variants are intended to be non-limiting, such thatrecitation of items in a list is not to the exclusion of other likeitems that can be substituted or added to the listed items.

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing amounts, sizes, dimensions,proportions, shapes, formulations, parameters, percentages, parameters,quantities, characteristics, and other numerical values used in thespecification and claims, are to be understood as being modified in allinstances by the term “about” even though the term “about” may notexpressly appear with the value, amount or range. Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thefollowing specification and attached claims are not and need not beexact, but may be approximate and/or larger or smaller as desired,reflecting tolerances, conversion factors, rounding off, measurementerror and the like, and other factors known to those of skill in the artdepending on the desired properties sought to be obtained by thepresently disclosed subject matter. For example, the term “about,” whenreferring to a value can be meant to encompass variations of, in someembodiments, ±100% in some embodiments ±50%, in some embodiments ±20%,in some embodiments ±10%, in some embodiments ±5%, in some embodiments±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from thespecified amount, as such variations are appropriate to perform thedisclosed methods or employ the disclosed compositions.

Further, the term “about” when used in connection with one or morenumbers or numerical ranges, should be understood to refer to all suchnumbers, including all numbers in a range and modifies that range byextending the boundaries above and below the numerical values set forth.The recitation of numerical ranges by endpoints includes all numbers,e.g., whole integers, including fractions thereof, subsumed within thatrange (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5,as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like)and any range within that range.

Although the foregoing subject matter has been described in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be understood by those skilled in the art thatcertain changes and modifications can be practiced within the scope ofthe appended claims.

That which is claimed:
 1. A device for measuring coagulation response ina blood sample, the device comprising a test cartridge comprising: afirst member having a first flat surface; and a second member having asecond flat surface positioned to face the first flat surface to definea space therebetween sized to allow a sample of blood to be introducedinto the space to contact the first flat surface and the second flatsurface, the first member configured to linearly move and oscillate tocause the first flat surface to oscillate relative to the second flatsurface to cause the sample of blood to coagulate and bind thereto, thesecond member configured to move from a stationary configurationresponsive to the movement of the first member via the coagulated sampleof blood, thereby changing mechanical displacement between the first andsecond members for measuring a coagulation response of the sample ofblood.
 2. The device of claim 1, wherein the test cartridge isconfigured to be disposable after use.
 3. The device of claim 1, furthercomprising a humidity control mechanism.
 4. The device of claim 3,wherein the humidity control mechanism comprises a sponge-like padinside a humidity pouch, and wherein the humidity pouch comprises aremovable cover.
 5. The device of claim 4, wherein the removable coveris configured to be removed to expose the sponge-like pad to an interiorenvironment of the test cartridge.
 6. The device of claim 1, furthercomprising a temperature control mechanism configured to maintain adesired temperature within the device.
 7. The device of claim 6, whereinthe temperature control mechanism comprises a heater.
 8. The device ofclaim 6, wherein the temperature control mechanism comprises a coolingdevice.
 9. The device of claim 1, wherein the test cartridge isconfigured to be coupled to a measuring device, and wherein the firstmember further comprises an engagement feature configured to engage witha drive mechanism in the measuring device.
 10. The device of claim 9,wherein the engagement feature comprises one or more of pinch contactribs or ridges.
 11. The device of claim 1, further comprising areceptacle configured to provide a path for the sample of blood to passfrom a blood introduction mechanism to the space between the first flatsurface and the second flat surface.
 12. The device of claim 11, furthercomprising the blood introduction mechanism, wherein the bloodintroduction mechanism comprises: an open top comprising a firstopening; a funnel portion; a flat bottom comprising a second openingsmaller than the first opening; and a lip attached to the funnelportion, wherein a desired amount of blood introduced to the open top isconfigured to pass through the blood introduction mechanism and into thereceptacle of the test cartridge, thereby providing the sample of bloodinto the test cartridge.
 13. The device of claim 1, wherein the firstand second members comprise a glass-filled thermoplastic polymer. 14.The device of claim 1, wherein the first and second flat surfaces areeach entirely flat.
 15. The device of claim 14, wherein the first membercomprises a first round plate, wherein the second member comprises asecond round plate, and wherein the first flat surface is disposed onthe first round plate and the second flat surface is disposed on thesecond round plate.
 16. The device of claim 1, wherein the first flatsurface and the second flat surface are parallel.
 17. The device ofclaim 1, wherein the mechanical displacement between the first andsecond members is configured to be optically detected for measuring thecoagulation response of the sample of blood.
 18. The device of claim 1,wherein mechanical displacement between the first and second membersdecreases as binding between the first and second flat surfacesincreases resulting from increased strength in clotting of the sample ofblood.
 19. The device of claim 1, further comprising a measuring deviceconfigured to be removably coupled to the test cartridge.
 20. The deviceof claim 19, wherein the measuring device comprises a drive mechanismconfigured to be coupled to the first member to cause the first flatsurface to oscillate relative to the second flat surface.
 21. The deviceof claim 20, wherein the drive mechanism comprises a motor configured tomove the first member.
 22. The device of claim 21, wherein the motorcomprises a piezo motor.
 23. The device of claim 21, further comprisinga processor connected to the motor and configured to control operationof the motor in a predetermined manner.
 24. The device of claim 19,wherein the measuring device further comprises a second drive mechanismconfigured to be coupled to the second member to cause the second flatsurface to move.
 25. The device of claim 19, wherein the measuringdevice comprises one or more optical sensors configured to measureinformation indicative of the coagulation response of the sample ofblood.
 26. The device of claim 19, wherein the measuring devicecomprises a display configured to display information related to thecoagulation response of the sample of blood.
 27. The device of claim 19,wherein the measuring device comprises a communications interfaceconfigured to wirelessly transmit information from the measuring device.28. The device of claim 19, wherein the measuring device is configuredto continually measure visco elasticity of the sample of blood over timeto monitor changes over time of the coagulation response of the sampleof blood.
 29. The device of claim 1, wherein the first member isconfigured to be moved at a first speed to permit optical detectionrelated to binding of the sample of blood to the first and second flatsurfaces to determine platelet response during coagulation.
 30. Thedevice of claim 29, wherein the first member is configured to besubsequently moved at a second speed slower than the first speed topermit optical detection of a level of coagulation of the sample ofblood as indicative of a fibrin polymerization response.
 31. The deviceof claim 1, further comprising one or more pull tabs configured to beremoved from the test cartridge before the sample of blood isintroduced.
 32. The device of claim 1, further comprising memoryconfigured to store information about the coagulation response.
 33. Thedevice of claim 1, wherein the second member is configured to moverelative to the first member in a manner causing the second member tomove due to visco elastic coupling between the sample of blood and thefirst and second flat surfaces, and wherein visco elastic properties ofthe sample of blood are determined from the movement of the secondmember.
 34. The device of claim 1, wherein strain rates are configuredto be detected by movement of the second member relative to the firstmember caused by visco elastic coupling between the first and secondflat surfaces caused by the sample of blood, and wherein the coagulationresponse is determined by an inference analysis based on viscoelasticity of the sample of blood determined from mechanical couplingbetween the first and second flat surfaces and the detected strainrates.